Download Recurrent Pregnancy Loss

Recurrent Pregnancy Loss
부산백병원 산부인과
R1. 조인호
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Spontaneous pregnancy loss is, in fact, the most
common complicadon of pregnancy.
About 70% of human conceptions fail to achieve
viability
estimated 50% are lost before the first missed
menstrual period.
Most of preg. Losses are unrecognized.
Actual rate of preg. Loss after implantation is 31%(by
hCG assay)
Clinically recognized, loss occures in 15% before
20wks of gestation.
부산백병원 산부인과
Recurrent abortion
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Definition : 3 or more clinically recognized pregnancy
losses before 20wks from LMP.
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->incidence: 1/300
Clinical investigation should be started after two
consecutive spontaneous abortions, especially
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when fetal heart activity had been identified prior to the
pregnancy loss
when the women is older than 35 yrs of age
when the couple has had difficulty conceiving
부산백병원 산부인과
Proposed Etiologies
Table 28.1
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Genetic Factors
Anatomic Factors
Endocrine Factors
Infectious Factors
Immunologic Factors
Other Factors
부산백병원 산부인과
3.5-5%
12-16%
17-20%
0.5-5%
20-50%
10%
Genetic Factors
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Balanced translocations : the most common inborn
parental chromosomal abnormalities.
Monosomy : in vitro fertilization
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Viable only that of X-chromosome
Trisomy : (13, 18, 21) tolerated than monosomy.
Family history alone , or history of prior term births is
not sufficient to rule out a potential parental
chromosomal abnomiality.
Others : inversion , insertion
Recently, inherited thrombophilias in recurrent
pregnancy loss.
부산백병원 산부인과
Inherited Thrombophilias
부산백병원 산부인과
Anatomic Abnormalities
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uterine cervix ,the uterine body
Congenital Uterine anomaly의 종류
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intrauterine septum (exposure DES)
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complete mullerian duct fusion
incomplete septum resorption
uterine cervical anomalies
60% risk for spontaneous abortion
Occur during 2nd trimester.
Acquired anomaly의 종류
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Adhesions, uterine fibroids, endometriosis
부산백병원 산부인과
Endocrine Abnormalities
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Normal pregnancies : luteal-placental shift (7 to 9
weeks of gestation)
Luteal-phase insufficiency or luteal-phase defects
(LPDs)
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LH secretion의 effect
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inadequate or improperly timed endometrial development at
potential implantation sites.
Developing oocyte
Endometrium
PCOS -> elevated androgen levels.
DM -> directly linked to embryonic damage
Thyroid disease
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Antithyroid antibodies(ATA)
부산백병원 산부인과
Maternal Infections
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Most controversial
Most common form
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Mycoplasma, Ureaplasma, Chlamydia, β- Streptococcus
response to pathologic organism로 인한 immunologic
activation -> recurrent preg. Loss
부산백병원 산부인과
Immunologic phenomena
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Innate response : first line of defense
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C’ activation phagocytosis by macrophage, lysis by NK cell
by (TCR-γδ+)T-cell.
Acquired immune respnose:
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Antigen specific
Mediated by T, B cell
부산백병원 산부인과
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Cellular Immunity
Humoral Immunity
부산백병원 산부인과
부산백병원 산부인과
부산백병원 산부인과
부산백병원 산부인과
부산백병원 산부인과
Cellular immunity
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Resident endometrial and decidual cells
Immune cell education and homing
Antigen presentation
In situ immunoregulation
부산백병원 산부인과
Resident endometrial and decidual cells
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T cells, macrophage, and NK-like cells, but very few
B cells
TCR-αβ + and TCR-γδ+ cells are present, TCR-γδ+
cells increase in early pregnancy.
NK-like, large granular lymphocytes (decidual NK
cells) accumulate at sites of Implantation.
NKT cells and suppressor macrophage.
부산백병원 산부인과
Immune cell education and homing
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The implanting fetus represents the most common
model of allograft acceptance.
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Thymic versus extrathymic education.
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Possible in situ education and maintenance.
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Integrins and vascular ligand pairs and mucosal
homing.
부산백병원 산부인과
Antigen Presentation at the Maternal-Fetal
tnterface
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implanting trophoblastic allograft could potentially
immune detection by the matemal host would be by
making itself antigenically invisible.
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Downregulation of expression of MHC encoded antigen.
Class II MHC molecules are not expressed in the
placenta.
Classic class 1 MHC molecules HLA-A and HLA-B
are not expressed in the placenta.
Extravillous cytotrophoblast cells express HLA-C,
HLA-E, and HLA-G.
부산백병원 산부인과
부산백병원 산부인과
In situ immunoregulation
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TH1- IFN-γ, IL-2, TNF-β, TNF-α -> harmful
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TH2- IL-4, IL-5, IL-6, IL-10 ,TNF-α -> normal
부산백병원 산부인과
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Hormonal immunomodulation
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Progesterone
Estrogen
Human chorionic gonadotropin (hCG)
Others
Tryptophan metabolism and indolamine 2,3-dioxygenase (IDO)
Leukemia-inhibiting factor (LIF)
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Blastocyte implantation에 필요함.
부산백병원 산부인과
Humoral Immune Mechanisms.
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Fetal antigens are recognized by the maternal immune system,
and humoral responses are mounted
Organ nonspecific autoantibody
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Anticardiolipin antibodies
Lupus anticoagulant
Anti-β2 glycoprotein 1 and (anti-β2) antibodies
Antiphosphatidlyserine antibodie'
Organ-specific autoantibodies
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Antithyroid antibodies
Antisperm antibodies
Antitrophoblast antibodies
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Blocking antibodies
HLA sharing
Trophoblast and lymphocyte cross-reactive antibodies (TLX)
부산백병원 산부인과
Ofher Factors
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Altered uterine receptivity (integrins, adhesion molecules)
Environmental
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Toxins
lllicitdrugs
Alcohol, cigarettes and caffeine
Placental abnormalities (circumvallate, marginate)
Medical illnesses (cardiac, renal, hematologic)
Male factors
Coitus
Exercise
Dyssynchronous fertilization
부산백병원 산부인과
Recurrent pregnancy loss (II)
2003. 9. 9
R1 박영미
Preconception Evaluation
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Hystory
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Physical examination
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Laboratory
부산백병원 산부인과
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Hystory
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Pattern, trimester, characteristics of prior pregnancy losses
History of subfertility or infertility
Menstrual history
Prior or current gynecologic or obstetric infections
Sings or symptoms of thyroid, prolactin, glucose tolerance,
hyperandrogenic disorders (PCOS)
Personal or familial thrombotic history
Features associated with the antiphospholipid syndrome
(thrombosis, false-positive test results for syphilis)
부산백병원 산부인과
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Other automimune disorder
Medication
Environmental exposures, illicit and common drug use
(particularly caffeine, alcohol, cigarettes, in utero DES exposure)
Genetic relationship between reproductive partners
Family history of recurrent spontaneous abortion, obstetric
complications, or any syndrome associated with embryonic or
fetal losses
Previous diagnostic tests and treatments
부산백병원 산부인과
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Physical examination
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obesity
hirsuitism and acanthosis
thyroid examination
breast examination and galactorrhea
pelvic examination
anatomy
infection
trauma
estrogenization
부산백병원 산부인과
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Laboratory
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parental peripheral blood karyotype
hysterosalpingography, followed by hysteroscopy
or
laparoscopy, if indicated
Luteal-phase endometrial biopsy
Anticardiolipin antibody level
Thyroid-stimulating hormone level, serum prolactin level, if
indicated
Lupus anticoagulant
Complete blood count with platelets
부산백병원 산부인과
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Tests with unproven or unknown utility
- evaluation of ovarian reserve using day 3 serum follicle-stimulating hormone
- testing for serologic evidence of PCOS using LH or androgen values levels
or the clomiphene challenge test
testing for peripheral evidence of Th1 and Th2 cytokine dysregulation
- testing for hypercoagulability using the aPTT or for the presence of
a hereditary thrombophilia
- the prevalence and activity of peripheral NK cells
testing for the presence of a variety of
autoantibodies (antiphosphatidylserineand anti-ϐ2 glycoprotein1) ->
placental pathology
- testing for antithyroid antibodies
testing for congenital or acquired defects in homocysteine metabolism ->
the measurement of blood levels of homocysteine
- cervical cultures for mycoplasma, ureaplasma and chlamydia
부산백병원 산부인과
Postconception Evaluation
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close monitoring
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to provide psychological support and to confirm intrauterine
pregnancy and its viability
serum levels of ϐ-hCG
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serum ϐ-hCG levels should be serially monitored from the
time of a missed menstrual period until the level is about
1500 mIU/mL , at which time an ultrasonographic scan is
performed and blood sampling is discontinued.
부산백병원 산부인과
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ultrasonographic examination
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maternal serum for a-fetoprotein assessment
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ultrasonographic assessment is then performed every 2weeks until the
gestational age at which previous pregnancies were aborted
at 16-18 weeks of gestation
amniocentesis
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to assess the fetal karyotype after the pregnancy has progressed past the
time of prior losses
부산백병원 산부인과
Therapy
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Genetic abnormalities
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Anatomic Anomalies
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Endocrine Abnormalities
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Infection
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Immunologic Factors
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Antithrombotic Therapy
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Psychological Support
부산백병원 산부인과
Genetic abnormalities
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antithrombotic therapy
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assisted reproductive technologies, including PGD (preimplantation
genetic diagnosis)
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for patients with inherited thrombophilias
the removal of a single cell from an in vitro-matured embryo
Genetic testing can be performed on this cell to rule out gross
chromosomal abnormalities or the presence of specific genetic diseases
embryos that are diagnosed with genetic abnormalities would not be
chosen for replacement into the uterine cavity
genetically normal would be considered appropriate for transfer into the
uterus.
use of either donor oocyte or donor sperm
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depending on the affected partner
부산백병원 산부인과
Anatomic Anomalies
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hysteroscopic resection
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ultrasonographically guided transcervical metroplasty
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submucous leiomyomas, intrauterine adhesions, intrauterine septa, patients with DES
exposure, hypoplastic uteri, complicating septal anomalies
in the operating room, general anesthesia
safe and effective, ambulatory, office-based procedures
placement of a cervical cerclage
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for patients with a history of loss secondary to cervical incompetence
performed early in the second trimester
부산백병원 산부인과
Endocrine Abnormalities
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luteal-phase insufficiency
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stimulating folliculogenesis with ovulation induction
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insulin-sensitizing agents
overt diabetes mellitus
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luteal-phase support with progesterone
PCOS, hyperandrogenism, hyperinsullinemia
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hyper androgen and LH hypersecretion disorders, especially following pituitary desensitization
with gonadotropin-releasing hormone agonist therapy - this treatment also remains
controversial
prepregnancy glycemic control
hypothyroidism
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thyroid hormone replacement with synthroid
부산백병원 산부인과
Infection
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an infectious organism has been identified
appropriate antibiotics should be administered to
both partners
followed by posttreatment culture
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empiric antibiotic treatment has been used for couples with
recurrent abortion.
its efficacy is unproven
부산백병원 산부인과
Immunologic Factors
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Immunostimulating Therapies-Leukocyte
Immunization
Immunosuppressive Therapies
부산백병원 산부인과
Immunostimulating Therapies-Leukocyte
Immunization
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stimulation of the maternal immune system using
alloantigens on either paternal or pooled donor leukocytes
a number of reports support possible mechanism for
potential therapeutic value
however, there is no credible clinical or laboratory method to
identify a specific individual who may benefit from such
therapy
leukocyte immunization also poses significant risk to both
the mother and her fetus
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graft-versus-host disease, severe intrauterine growth
retardation, and autoimmune and isoimmune complications
부산백병원 산부인과
Immunosuppressive Therapies
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To antiphospholipid antibodies and to inappropriate cellular
immunity toward the implanting fetus
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intravenous immunoglobulin
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progesterone
부산백병원 산부인과
intravenous immunoglobulin
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theory
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Mechanism
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decreased autoantibody production and increased autoantibody
clearance, T-cell and Fc receptor regulation, complement
inactivation, enhanced T-cell suppressor function, decreased Tcell adhesion to the extracellular matrix, and downregulation of Th1
cyokine synthesis
disadvantage
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an overzealous immune reactivity to their implanting fetus
expensive, invasive, and time-consuming, requiring multiple
intravenous infusions over the course of pregnancy
side effects
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nausea, headache, myalgias, hypotension, anaphylaxis
부산백병원 산부인과
progesterone
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Mechanism
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inhibits Th1 immunity
shift from Th1-to Th2 type responses
administered
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intramuscularly
intravaginally
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may increase local, intrauterine concentration
averting any adverse systemic side effects
부산백병원 산부인과
Antithrombotic Therapy
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the combined use of low-dose aspirin (75-80mg/dl) and
subcutaneous unfractionated heparin (5000unit twice daily)
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antiphospholipid antibody syndrome
aspirin (80mg every day) beginning
after pregnancy has been confirmed, 5000 IU unfractionated sodium hearin
is administered subcutaneously twice daily, throughout gestation.
an aPTT should be obtained weekly
increased risk for preterm labor, premature rupture of the membranes,
intrauterine growth restriction, intrauterine fetal demise, and preeclampsia.
gastirc bleeding, osteopenia, and abruptio placenta.
부산백병원 산부인과
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LMWH
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protein C concentrates
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increased antithrombotic ratio, fewer bleeding side effects. a
decreased incidence of thrombocytopenia and osteoporosis.
a long half-life, less frequent dosing and monitoring
favorable pregnancy outcome in a patient with a history of
thrombosis, recurrent fetal losses, and protein C deficiency
vitamins B6, B12 and folate
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important in homocysteine metabolism, and
hyperhomocysteinemia is linked to recurrent pregnancy loss
부산백병원 산부인과
Psychological Support
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guilt among patients with recurrent losses
the risk for major depression is increased greater than twofold among
women with spontaneous pregnancy loss, in most women, it arises in
the first weks after delivery
a caring and empathetic attitude is prerequisite to all healing.
referrals to support groups and counselors should be offered.
self-help measures, such as meditation, yoga, exercise, and
biofeedback, may also be useful.
부산백병원 산부인과
Prognosis
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the prognosis for successful pregnancy depends
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the potential underlying cause of pregnancy loss
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the unmber of prior losses.
부산백병원 산부인과
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the chance of a viable birth
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even after four prior losses : 60%
cytogenetic etiology : 20%-80%
corrected anatomic anomalies : 60%-90%
corrected endocrinologic abnormalities : higher than 90%
women receiving therapy for antiphospholipid antibodies :
70% - 90%
부산백병원 산부인과